The specific aims of this project during the request period of funding include: (a) to continue the development of complementary synthetic protocols which permit the stereoselective construction of a wide variety of 2'-deoxyribose and 2',3'-dideoxyribose derivatives of nucleosides from inexpensive, non-carbohydrate precursors; and (b) to prepare and evaluate novel nucleoside analogues which may exhibit significant anti-HIV activity. A number of novel methods are proposed for synthesizing purine nucleosides from glutamic acid. In addition, we propose to develop complementary methodology which permits the efficient construction of antiviral nucleosides from acyclic, achiral precursors. We also plan to evaluate the generality of employing enzyme-mediated reactions to resolve racemic nucleosides and thereby enable us to evaluate the antiviral activity of "unnatural" enantiomers of nucleosides. Finally, we will attempt to prepare a variety of 6-substituted pyrimidine nucleosides and evaluate their utility as antiviral agents.